Abstract
Venous malformations (VMs) are slow-flow malformations of the venous vasculature and are the most common type of vascular malformation with a prevalence of 1%. Germline and somatic mutations have been shown to contribute to VM pathogenesis, but how these mutations affect VM pathobiology is not well understood. The goal of this study was to characterize VM endothelial and mural cell expression by performing a comprehensive expression analysis of VM vasculature. VM specimens (n = 16) were stained for pan-endothelial, arterial, venous, and endothelial progenitor cell proteins; proliferation was assessed with KI67. Endothelial cells in the VM vessels were abnormally orientated and improperly specified, as seen by the misexpression of both arterial and endothelial cell progenitor proteins not observed in control vessels. Consistent with arterialization of the endothelial cells, VM vessels were often surrounded by multiple layers of disorganized mural cells. VM endothelium also had a significant increase in proliferative endothelial cells, which may contribute to the dilated channels seen in VMs. Together the expression analysis indicates that the VM endothelium is misspecified and hyperproliferative, suggesting that VMs are biologically active lesions, consistent with clinical observations of VM progression over time.
Highlights
The formation of blood vessels initiates with multipotent angioblasts differentiating into venous and arterial endothelial cells (ECs) that form a uniform primary plexus, a process known as vasculogenesis [1]
Venous malformations (VMs) endothelium has reduced and mislocalized expression of essential EC adhesion proteins Morphological analysis of VM tissues revealed that pathological vessels were dilated, irregularly-shaped vascular channels lined by disorganized endothelial cells with nuclei often oriented perpendicular to the lumen, suggesting defects in EC polarity or cell-cell associations (S1 Fig)
To evaluate the tight and adherens junctions, VM specimens were stained for VECADHERIN, CD31, and VEGFR2
Summary
The formation of blood vessels initiates with multipotent angioblasts differentiating into venous and arterial endothelial cells (ECs) that form a uniform primary plexus, a process known as vasculogenesis [1]. The plexus is remodeled and mural cells, pericytes, and vascular smooth muscle cells are recruited to stabilize and mature the blood vessels, a process known as angiogenesis. These processes may be dysregulated in vascular malformations. Vascular malformations are congenital disorders that result in the development of morphologically and architecturally abnormal vascular channels; their development has been suggested to be a result of disruptions in cell fate determination as well as endothelial cell-perivascular cell organization [2, 3]. Venous malformations (VMs) are slow-flow malformations of the venous vasculature [4,5,6].
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